System and method for neural stimulation

ABSTRACT

Various aspects provide an implantable device. In various embodiments, the device comprises at least one port, where each port is adapted to connect a lead with an electrode to the device. The device further includes a stimulation platform, including a sensing circuit connected to the at least one port to sense an intrinsic cardiac signal and a stimulation circuit connected to the at least one port via a stimulation channel to deliver a stimulation signal through the stimulation channel to the electrode. The stimulation circuit is adapted to deliver stimulation signals through the stimulation channel for both neural stimulation therapy and CRM therapy. The sensing and stimulation circuits are adapted to perform CRM functions. The device further includes a controller connected to the sensing circuit and the stimulation circuit to control the neural stimulation therapy and the CRM therapy. Other aspects and embodiments are provided herein.

RELATED APPLICATIONS

This application is related to U.S. patent application Ser. No.11/087,935 filed Mar. 23, 2005, now U.S. Pat. No. 7,660,628 to U.S.patent application Ser. No. 11/468,143 filed Aug. 29, 2006, now U.S.Pat. No. 7,801,604, the disclosures of which are hereby incorporated byreference in their entirety.

TECHNICAL FIELD

This application relates generally to medical devices and, moreparticularly, to systems, devices and methods to provide myocardial andneural stimulation.

BACKGROUND

Implanting a chronic electrical stimulator, such as a cardiacstimulator, to deliver medical therapy(ies) is known. Examples ofcardiac stimulators include implantable cardiac rhythm management (CRM)devices such as pacemakers, implantable cardiac defibrillators (ICDs),and implantable devices capable of performing pacing and defibrillatingfunctions. Implantable CRM devices provide electrical stimulation toselected portions of the heart in order to treat disorders of cardiacrhythm, generally referred to herein as CRM functions/therapy. Animplantable pacemaker, for example, is a CRM device that paces the heartwith timed pacing pulses. The pacing pulses can be timed from otherpacing pulses or sensed electrical activity. If functioning properly,the pacemaker makes up for the heart's inability to pace itself at anappropriate rhythm in order to meet metabolic demand by enforcing aminimum heart rate. Some CRM devices synchronize pacing pulses deliveredto different areas of the heart in order to coordinate the contractions.Coordinated contractions allow the heart to pump efficiently whileproviding sufficient cardiac output. Clinical data has shown thatcardiac resynchronization, achieved through synchronized biventricularpacing, results in a significant improvement in cardiac function.Cardiac resynchronization therapy improves cardiac function in heartfailure patients.

Heart failure patients have abnormal autonomic balance, which isassociated with LV dysfunction and increased mortality. Modulation ofthe sympathetic and parasympathetic nervous systems has potentialclinical benefit in preventing remodeling and death in heart failure andpost-MI patients. Direct electrical stimulation can activate thebaroreflex, inducing a reduction of sympathetic nerve activity andreducing blood pressure by decreasing vascular resistance. Sympatheticinhibition and parasympathetic activation have been associated withreduced arrhythmia vulnerability following a myocardial infarction,presumably by increasing collateral perfusion of the acutely ischemicmyocardium and decreasing myocardial damage.

SUMMARY

Various aspects of the present subject matter provide an implantabledevice. In various embodiments, the device comprises at least one port,where each port is adapted to connect a lead with an electrode to thedevice. The device further includes a stimulation platform, including asensing circuit connected to the at least one port to sense an intrinsiccardiac signal and a stimulation circuit connected to the at least oneport via a stimulation channel to deliver a stimulation signal throughthe stimulation channel to the electrode. The stimulation circuit isadapted to deliver stimulation signals through the stimulation channelfor both neural stimulation therapy and CRM therapy. The sensing andstimulation circuits are adapted to perform CRM functions. The devicefurther includes a controller connected to the sensing circuit and thestimulation circuit to control the neural stimulation therapy and theCRM therapy.

Various aspects of the present subject matter provide a method foroperating an implantable device to deliver a desired stimulation signalthrough a stimulation channel to an electrode. In an embodiment of themethod, a desired therapy to be delivered through the stimulationchannel to the electrode is determined. Upon determining that a cardiacrhythm management (CRM) therapy is desired, a CRM stimulation signal isdelivered through the stimulation channel to the electrode to capture aheart muscle. Upon determining that a neural stimulation therapy isdesired, a neural stimulation signal is delivered through thestimulation channel to the electrode to elicit a neural response.

Various aspects of the present subject matter provide a method formaking an implantable medical device. In an embodiment of the method, acontroller is connected to a memory, to a sensing module adapted tosense intrinsic cardiac signals over a sensing channel from anelectrode, and to a stimulation module adapted to generate stimulationsignals on a stimulation channel to the electrode. Computer instructionsto be performed by the controller are stored in the memory. The computerinstructions include instructions to perform a neural stimulationtherapy using the stimulation module and to perform a cardiac rhythmmanagement (CRM) therapy using the sensing module and the stimulationmodule. The computer instructions further include instructions toreceive a therapy selection input, to generate a neural stimulationsignal on the stimulation channel to the electrode if the neuralstimulation therapy is selected, and to generate a CRM stimulationsignal on the stimulation channel to the electrode if the neural CRMtherapy is selected.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects will be apparent to persons skilled in the art upon reading andunderstanding the following detailed description and viewing thedrawings that form a part thereof, each of which are not to be taken ina limiting sense. The scope of the present invention is defined by theappended claims and their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B illustrate neural mechanisms for peripheral vascularcontrol.

FIG. 2 illustrates a heart.

FIG. 3 illustrates baroreceptors in the area of the carotid sinus,aortic arch and pulmonary artery.

FIG. 4 illustrates baroreceptors in and around a pulmonary artery.

FIG. 5 illustrates baroreceptor fields in the aortic arch, near theligamentum arteriosum and the trunk of the pulmonary artery.

FIG. 6 illustrates baroreflex adaptation using a relationship betweencarotid sinus pressure, sympathetic nerve activity (SNA) and meanarterial pressure (MAP).

FIG. 7 illustrates a diagram, representing stimulation parameters, aregion representing parameters capable of being used to perform CRMstimulation, a region representing parameters capable of being used toperform neural stimulation, and a region representing parameters capableof being used to perform both neural stimulation and CRM stimulation.

FIG. 8 is a graphical illustration of the relationship between a changein blood pressure and a rate of a stimulation signal.

FIG. 9A illustrates an implantable medical device with leads extendinginto a heart; and FIGS. 9B and 9C illustrate an implantable medicaldevice with endocardial and epicardial leads, respectively.

FIGS. 10A and 10B illustrate the right side and left side of the heart,respectively, and further illustrate cardiac fat pads which provideneural targets for some neural stimulation therapies.

FIG. 11 illustrates an embodiment of an implantable medical device.

FIG. 12 is a simplified schematic illustration of a pace module for thehardware platform illustrated in FIG. 11.

FIG. 13 illustrates a multi-channel embodiment of an implantable medicaldevice.

FIGS. 14A, 14B and 14C illustrate examples of waveforms used to providemyocardial and neural stimulation.

FIG. 15 illustrates a method to selectively provide myocardial and/orneural stimulation over a stimulation channel of the implantable medicaldevice.

FIG. 16 illustrates a waveform made up of monophasic pulse trains withalternating polarity as would be generated by a current source pulseoutput circuit.

FIG. 17 illustrates a biphasic waveform with alternating polarity aswould be generated by a current source pulse output circuit.

FIG. 18 illustrates a waveform made up of monophasic pulse trains withalternating polarity as would be generated by a capacitive dischargepulse output circuit.

FIG. 19 illustrates a biphasic waveform with alternating polarity aswould be generated by a capacitive discharge pulse output circuit.

FIG. 20 illustrates an embodiment of circuitry for deliveringstimulation pulse trains using a current source pulse output circuit.

FIG. 21 illustrates an embodiment of circuitry for deliveringstimulation pulse trains using a capacitive discharge pulse outputcircuit.

FIG. 22 is a system diagram of an exemplary neural stimulator.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

Disclosed herein is a device in which a common hardware platform is usedto provide both neural stimulation and CRM stimulation, also referred toherein as myocardial stimulation, thus reducing the hardwarerequirements to perform both CRM and NS therapies. The reduced hardwarerequirements can reduce the cost and size of the device. Various deviceembodiments include hardware capable of alternating between myocardialstimulation and neural stimulation, and various device embodimentsinclude hardware to provide a common stimulation waveform capable ofsimultaneously activating the myocardium and the nerve. For example, oneembodiment switches between stimulation modes, in which the devicedelivers a stimulating waveform suitable for cardiac pacing, neuralstimulation, or both cardiac pacing and neural stimulation is delivered.These different stimulation waveforms can be delivered at differentsites (through the CRM lead(s) or through the neural stimulationlead(s)). In some embodiments, neural stimulation waveforms aredelivered through dedicated leads and cardiac pacing waveforms aredelivered through dedicated leads; and in some embodiments, the neuralstimulation and cardiac pacing waveforms are delivered at alternatingtimes through the same lead(s).

Some CRM devices have the ability in hardware to provide electricalstimulation at the appropriate amplitude and frequency for neuralstimulation such as burst pacing at frequencies up to 50 Hz. Examples ofneural stimulation leads include an expandable stimulation lead placedin the pulmonary artery in the proximity of a high concentration ofbaroreceptors, an intravascularly-inserted lead placed proximal to andadapted to transvascularly stimulate a cardiac fat pad, an epicardiallead placed in a cardiac fat pad, a cuff electrode placed around a nervetrunk such as the aortic, carotid or vagus nerve, and anintravascularly-inserted lead placed proximal to and adapted totransvascularly stimulate a nerve trunk such as the aortic, carotid orvagus nerve.

In various embodiments, the implantable device uses a lead positioned toprovide either myocardial stimulation, to provide neural stimulation, orto simultaneously provide both myocardial stimulation and neuralstimulation by delivering a waveform through the appropriately placedstimulation lead that stimulates the myocardium and the nerve. Thus,through a judicious selection of stimulation waveforms, this embodimentdoes not switch between modes, but accomplishes simultaneous cardiac andneural stimulation. Other waveforms are applied if it is desired toprovide only cardiac pacing or neural stimulation, but not both.

The stimulation device of the present subject matter uses a common orshared hardware platform to provide both CRM therapy (pacing, CRT, etc.)and neural stimulation through either a common or an independent lead.Some device embodiments switch between output modes, using the samehardware to provide cardiac pacing and neural stimulation. Typically,cardiac pacing occurs at a relatively lower frequency and largeramplitude than neural stimulation.

CRM therapy (such as brady pacing and/or CRT) is capable of beingprovided in conjunction with neural stimulation (such as anti-remodelingtherapy) without requiring additional hardware than that which alreadyexists in CRM hardware. Various embodiments use existing CRM outputchannel(s) adapted to exclusively provide neural stimulation, useexisting CRM output channel(s) adapted to alternate between cardiac andneural stimulation, and use existing CRM output channel(s) adapted tosimultaneously provide cardiac and neural stimulation.

The stimulation platform for an existing CRM device retains the existingpulse generator, pacing algorithms, and output circuitry. In anembodiment, the device intermittently suspends cardiac pacing anddelivers neural stimulation using a shared platform. In otherembodiments, an existing CRM lead is placed in a location so as toprovide either cardiac or neural stimulation, or both, depending on thestimulating waveform.

The following disclosure provides a discussion of physiology andexamples of therapies capable of being performed by the present subjectmatter, and further provides a discussion of an implantable medicaldevice and methods according to the present subject matter.

Physiology

Heart Failure

Heart failure refers to a clinical syndrome in which cardiac functioncauses a below normal cardiac output that can fall below a leveladequate to meet the metabolic demand of peripheral tissues. Heartfailure may present itself as congestive heart failure (CHF) due to theaccompanying venous and pulmonary congestion. Heart failure can be dueto a variety of etiologies such as ischemic heart disease.

Hypertension

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure, which can contribute to heart failure. Hypertension generallyrelates to high blood pressure, such as a transitory or sustainedelevation of systemic arterial blood pressure to a level that is likelyto induce cardiovascular damage or other adverse consequences.Hypertension has been arbitrarily defined as a systolic blood pressureabove 140 mm Hg or a diastolic blood pressure above 90 mm Hg.Consequences of uncontrolled hypertension include, but are not limitedto, retinal vascular disease and stroke, left ventricular hypertrophyand failure, myocardial infarction, dissecting aneurysm, andrenovascular disease.

A large segment of the general population, as well as a large segment ofpatients implanted with pacemakers or defibrillators, suffer fromhypertension. The long term mortality as well as the quality of life canbe improved for this population if blood pressure and hypertension canbe reduced. Many patients who suffer from hypertension do not respond totreatment, such as treatments related to lifestyle changes andhypertension drugs.

Cardiac Remodeling

Following myocardial infarction (MI) or other cause of decreased cardiacoutput, a complex remodeling process of the ventricles occurs thatinvolves structural, biochemical, neurohormonal, and electrophysiologicfactors. Ventricular remodeling is triggered by a physiologicalcompensatory mechanism that acts to increase cardiac output due toso-called backward failure which increases the diastolic fillingpressure of the ventricles and thereby increases the so-called preload(i.e., the degree to which the ventricles are stretched by the volume ofblood in the ventricles at the end of diastole). An increase in preloadcauses an increase in stroke volume during systole, a phenomena known asthe Frank-Starling principle. When the ventricles are stretched due tothe increased preload over a period of time, however, the ventriclesbecome dilated. The enlargement of the ventricular volume causesincreased ventricular wall stress at a given systolic pressure. Alongwith the increased pressure-volume work done by the ventricle, this actsas a stimulus for hypertrophy of the ventricular myocardium. Thedisadvantage of dilatation is the extra workload imposed on normal,residual myocardium and the increase in wall tension (Laplace's Law)which represent the stimulus for hypertrophy. If hypertrophy is notadequate to match increased tension, a vicious cycle ensues which causesfurther and progressive dilatation.

As the heart begins to dilate, afferent baroreceptor and cardiopulmonaryreceptor signals are sent to the vasomotor central nervous systemcontrol center, which responds with hormonal secretion and sympatheticdischarge. It is the combination of hemodynamic, sympathetic nervoussystem and hormonal alterations (such as presence or absence ofangiotensin converting enzyme (ACE) activity) that ultimately accountfor the deleterious alterations in cell structure involved inventricular remodeling. The sustained stresses causing hypertrophyinduce apoptosis (i.e., programmed cell death) of cardiac muscle cellsand eventual wall thinning which causes further deterioration in cardiacfunction. Thus, although ventricular dilation and hypertrophy may atfirst be compensatory and increase cardiac output, the processesultimately result in both systolic and diastolic dysfunction. It hasbeen shown that the extent of ventricular remodeling is positivelycorrelated with increased mortality in post-MI and heart failurepatients.

Nervous System

The automatic nervous system (ANS) regulates “involuntary” organs, whilethe contraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscle around bloodvessels, for example.

The ANS includes the sympathetic nervous system and the parasympatheticnervous system. The sympathetic nervous system is affiliated with stressand the “fight or flight response” to emergencies. Among other effects,the “fight or flight response” increases blood pressure and heart rateto increase skeletal muscle blood flow, and decreases digestion toprovide the energy for “fighting or fleeing.” The parasympatheticnervous system is affiliated with relaxation and the “rest and digestresponse” which, among other effects, decreases blood pressure and heartrate, and increases digestion to conserve energy. The ANS maintainsnormal internal function and works with the somatic nervous system.

The heart rate and force is increased when the sympathetic nervoussystem is stimulated, and is decreased when the sympathetic nervoussystem is inhibited (the parasympathetic nervous system is stimulated).FIGS. 1A and 1B illustrate neural mechanisms for peripheral vascularcontrol. FIG. 1A generally illustrates afferent nerves to vasomotorcenters. An afferent nerve conveys impulses toward a nerve center. Avasomotor center relates to nerves that dilate and constrict bloodvessels to control the size of the blood vessels. FIG. 1B generallyillustrates efferent nerves from vasomotor centers. An efferent nerveconveys impulses away from a nerve center.

Stimulating the systematic and parasympathetic nervous systems can haveeffects other than heart rate and blood pressure. For example,stimulating the sympathetic nervous system dilates the pupil, reducessaliva and mucus production, relaxes the bronchial muscle, reduces thesuccessive waves of involuntary contraction (peristalsis) of the stomachand the motility of the stomach, increases the conversion of glycogen toglucose by the liver, decreases urine secretion by the kidneys, andrelaxes the wall and closes the sphincter of the bladder. Stimulatingthe parasympathetic nervous system (inhibiting the sympathetic nervoussystem) constricts the pupil, increases saliva and mucus production,contracts the bronchial muscle, increases secretions and motility in thestomach and large intestine, and increases digestion in the smallintention, increases urine secretion, and contracts the wall and relaxesthe sphincter of the bladder. The functions associated with thesympathetic and parasympathetic nervous systems are many and can becomplexly integrated with each other.

Baroreflex is a reflex triggered by stimulation of a baroreceptor. Abaroreceptor includes any sensor of pressure changes, such as sensorynerve endings in the wall of the auricles of the heart, vena cava,aortic arch and carotid sinus, that is sensitive to stretching of thewall resulting from increased pressure from within, and that functionsas the receptor of the central reflex mechanism that tends to reducethat pressure. Clusters of nerve cells can be referred to as autonomicganglia. These nerve cells can also be electrically stimulated to inducea baroreflex, which inhibits the sympathetic nerve activity andstimulates parasympathetic nerve activity. Autonomic ganglia thus formspart of a baroreflex pathway. Afferent nerve trunks, such as the vagus,aortic and carotid nerves, leading from the sensory nerve endings alsoform part of a baroreflex pathway. Stimulating a baroreflex pathwayand/or baroreceptors inhibits sympathetic nerve activity (stimulates theparasympathetic nervous system) and reduces systemic arterial pressureby decreasing peripheral vascular resistance and cardiac contractility.Baroreceptors are naturally stimulated by internal pressure and thestretching of vessel wall (e.g. arterial wall).

Some aspects of the present subject matter locally stimulate specificnerve endings in arterial walls rather than stimulate afferent nervetrunks in an effort to stimulate a desired response (e.g. reducedhypertension) while reducing the undesired effects of indiscriminatestimulation of the nervous system. For example, some embodimentsstimulate baroreceptor sites in the pulmonary artery. Some embodimentsof the present subject matter involve stimulating baroreceptor sites ornerve endings in the aorta and the chambers of the heart, and someembodiments of the present subject matter involve stimulating anafferent nerve trunk, such as the vagus, carotid and aortic nerves. Someembodiments stimulate afferent nerve trunks using a cuff electrode, andsome embodiments stimulate afferent nerve trunks using an intravascularlead positioned in a blood vessel proximate to the nerve, such that theelectrical stimulation passes through the vessel wall to stimulate theafferent nerve trunk.

FIG. 2 illustrates a heart 201, a superior vena cava 202, an aortic arch203, and a pulmonary artery 204 for providing a contextual relationshipwith the illustrations in FIGS. 3-5. As is discussed in more detailbelow, the pulmonary artery 204 includes baroreceptors. A lead iscapable of being intravascularly inserted through a peripheral vein andthrough the tricuspid valve into the right ventricle of the heart (notexpressly shown in the figure) similar to a cardiac pacemaker lead, andcontinue from the right ventricle through the pulmonary valve into thepulmonary artery. A portion of the pulmonary artery and aorta areproximate to each other. Various embodiments stimulate baroreceptors inthe aorta using a lead intravascularly positioned in the pulmonaryartery. Thus, according to various aspects of the present subjectmatter, the baroreflex is stimulated in or around the pulmonary arteryby at least one electrode intravascularly inserted into the pulmonaryartery. Alternatively, a wireless stimulating device, with or withoutpressure sensing capability, may be positioned via catheter into thepulmonary artery. Control of stimulation and/or energy for stimulationmay be supplied by another implantable or external device viaultrasonic, electromagnetic or a combination thereof. Aspects of thepresent subject matter provide a relatively noninvasive surgicaltechnique to implant a baroreflex stimulator intravascularly into thepulmonary artery.

FIG. 3 illustrates baroreceptors in the area of the carotid sinus 305,aortic arch 303 and pulmonary artery 304. The aortic arch 303 andpulmonary artery 304 were previously illustrated with respect to theheart in FIG. 2. As illustrated in FIG. 3, the vagus nerve 306 extendsand provides sensory nerve endings 307 that function as baroreceptors inthe aortic arch 303, in the carotid sinus 305 and in the common carotidartery 310. The glossopharyngeal nerve 308 provides nerve endings 309that function as baroreceptors in the carotid sinus 305. These nerveendings 307 and 309, for example, are sensitive to stretching of thewall resulting from increased pressure from within. Activation of thesenerve endings reduce pressure. Although not illustrated in the figures,the atrial and ventricular chambers of the heart also includebaroreceptors. Cuffs have been placed around afferent nerve trunks, suchas the vagal nerve, leading from baroreceptors to vasomotor centers tostimulate the baroreflex. According to various embodiments of thepresent subject matter, afferent nerve trunks can be stimulated using acuff or intravascularly-fed lead positioned in a blood vessel proximateto the afferent nerves.

FIG. 4 illustrates baroreceptors in and around a pulmonary artery 404.The superior vena cava 402 and the aortic arch 403 are also illustrated.As illustrated, the pulmonary artery 404 includes a number ofbaroreceptors 411, as generally indicated by the dark area. Furthermore,a cluster of closely spaced baroreceptors is situated near theattachment of the ligamentum arteriosum 412. FIG. 4 also illustrates theright ventricle 413 of the heart, and the pulmonary valve 414 separatingthe right ventricle 413 from the pulmonary artery 404. According tovarious embodiments of the present subject matter, a lead is insertedthrough a peripheral vein and threaded through the tricuspid valve intothe right ventricle, and from the right ventricle 413 through thepulmonary valve 414 and into the pulmonary artery 404 to stimulatebaroreceptors in and/or around the pulmonary artery. In variousembodiments, for example, the lead is positioned to stimulate thecluster of baroreceptors near the ligamentum arteriosum 412. FIG. 5illustrates baroreceptor fields 511 in the aortic arch 503, near theligamentum arteriosum 512 and the trunk of the pulmonary artery 504.Some embodiments position the lead in the pulmonary artery to stimulatebaroreceptor sites in the aorta.

Nerves can adapt to stimulation, such that the effectiveness ofcontinuous stimulation diminishes over time. Embodiments of the presentsubject matter provide neural stimulation that accounts for neuraladaption. FIG. 6 illustrates baroreflex adaptation using a relationshipbetween carotid sinus pressure 615, sympathetic nerve activity (SNA) 616and mean arterial pressure (MAP) 617. Internal pressure and stretchingof the arterial wall, such as that which occurs at the carotid sinus,naturally activates the baroreflex and the baroreflex inhibits SNA. Thecarotid sinus pressure, the SNA and the MAP are illustrated for thefollowing four time segments: (1) relatively low and constant carotidsinus pressure 615 indicated at 618; (2) relatively high and constantcarotid sinus pressure 615 indicated at 619; (3) relatively high andpulsed carotid sinus pressure 615 indicated at 620; and (4) a return toa relatively high and constant carotid sinus pressure 615 indicated at621. When the carotid sinus pressure is relatively low and constant, asillustrated at 618, the SNA is relatively high and constant, and thepulsating MAP is relatively high. When the carotid sinus pressure isincreased to a relatively high and constant pressure at transition 622,the SNA and MAP initially decrease due to the baroreflex and thenincreases due to the quick adaptation of the baroreflex to the increasedcarotid sinus pressure. However, when the carotid sinus pressurepulsates similar to naturally-occurring blood pressure pulses, asillustrated at 620, the SNA and MAP decrease to relatively low levelsand are maintained at these relatively low levels. When the carotidsinus pressure changes from a pulsed to constant pressure at transition623, the SNA and MAP both increase again due to the adaptation of thebaroreflex. Various embodiments modulate the neural stimulation to mimicthe effects of the naturally-occurring pulse pressure and preventadaptation. For example, the amplitude, frequency, wave morphology,burst frequency and/or duration can be adjusted to abate adaptation.

Therapies

Neural stimulation may be delivered by an implantable device with orwithout delivery of other therapies. For example, a combination ofneural stimulation and myocardial stimulation by a cardiac rhythmmanagement (CRM) device may be used in a number of therapies, some ofwhich are discussed below. For example, combining neural stimulationwith CRM therapy provides benefits in treating hypertension, andcombining neural stimulation with cardiac rhythm therapy (CRT) providesbenefits in treating cardiac remodeling.

Parameters associated with neural stimulation signals include amplitude,frequency, burst frequency, pulse width, and morphology/waveform. FIG. 7illustrates a diagram, representing stimulation parameters 724, a region725 representing parameters capable of being used to perform CRMstimulation, a region 726 representing parameters capable of being usedto perform neural stimulation, and a region 727 representing parameterscapable of being used to perform both neural stimulation and CRMstimulation. Thus, FIG. 7 illustrates that some combinations of valuesfor these parameters will result in both myocardial and neuralstimulation, other combinations of values for these parameters willresult in myocardial stimulation and not neural stimulation, and othercombinations of values for these parameters will result in neuralstimulation and not myocardial stimulation. Embodiments of the presentsubject matter adjust the stimulation parameters to selectivelystimulate the myocardium, the nerve system, or both the myocardium andthe nerve system.

For example, nerves are generally depolarized with a higher frequencysignal than is typically used to capture myocardial tissue. FIG. 8 is agraphical illustration of the relationship between a change in bloodpressure and a rate of a stimulation signal. The figure illustrates thatthe frequency of the stimulation signal significantly affects thedecrease in blood pressure, which is a surrogate baroreflex parameterindicating the inhibition of SNA. The figure illustrates that a maximumdecrease in blood pressure occurs at a stimulation frequency within arange from about 64 to about 256 Hz, and occurs approximately at 128 Hz.Some known CRM devices are capable of providing burst pacing capable ofcapturing myocardial tissue and at a frequency (e.g. 50 Hz) sufficientto elicit nerve depolarization. Various embodiments adjust thefrequency, amplitude and/or morphology of the burst pacing according astimulation mode to either stimulate the myocardia and not the nervoussystem, to stimulate both the myocardia and the nervous system, and tostimulate the nervous system but not the myocardia.

Various embodiments of pace or stimulator modules used in theimplantable medical device of the present subject matter modulate thefrequency of the stimulation signal to modulate the blood pressure tomimic the effects of a naturally-occurring pulse. Various embodimentsstimulate with a frequency between approximately 8 Hz and approximately512 Hz, or various ranges within this range such as approximately 16 Hzto approximately 128 Hz, approximately 32 Hz to approximately 128 Hz,for example. Other embodiments modulate other parameters of thestimulation signal to mimic the effects of the naturally-occurringpulse, and thus prevent or reduce adaptation to neural stimulation. Bypreventing the baroreflex from adapting to increased baroreflexactivity, for example, long-term baroreflex stimulation can be used toachieve reflex reduction in hypertension. Varying the baroreflexstimulation maintains the reflex inhibition of SNA and abates (i.e.nullify or reduce in degree or intensity) adaptation to increasedbaroreflex activity that occurs during constant stimulation.

CRM Therapy

An example of CRM therapy is cardiac resynchronization therapy (CRT).However, CRM is not limited to CRT, as it includes a number of pacingmodes and defibrillation modes. Clinical data has shown that cardiacresynchronization therapy (CRT), achieved through synchronizedbiventricular pacing, results in a significant improvement in cardiacfunction. It has also been reported CRT can be beneficial in preventingand/or reversing the ventricular remodeling that often occurs in post-MIand heart failure patients. The combined application of remodelingcontrol therapy (RCT) by controlling ventricular activation with cardiacresynchronization pacing and anti-remodeling therapy (ART) bystimulating the baroreflex in order to inhibit sympathetic activityprovides a greater therapeutic benefit than either of them individually.The device controls ventricular activation through synchronized pacingof the right and left ventricles. In addition, the device may provide acombination of parasympathetic stimulation and sympathetic inhibition.Parasympathetic stimulation can be achieved through a nerve cuffelectrode placed around the cervical vagus nerve bundle, whilesympathetic inhibition can be achieved through baroreflex stimulation,either through a nerve cuff electrode placed around the aortic orcarotid sinus nerve, or though a stimulation lead designed to stimulatebaroreceptors in the pulmonary artery. The device controls the deliveryof RCT and ART independently in either an open-loop or closed-loopfashion, the latter based upon a cardiac function assessment performedby the device.

Implantable cardiac devices that provide electrical stimulation toselected chambers of the heart have been developed in order to treat anumber of cardiac disorders. A pacemaker, for example, is a device whichpaces the heart with timed pacing pulses, most commonly for thetreatment of bradycardia where the ventricular rate is too slow.Atrio-ventricular conduction defects (i.e., AV block) and sick sinussyndrome represent the most common causes of bradycardia for whichpermanent pacing may be indicated. If functioning properly, thepacemaker makes up for the heart's inability to pace itself at anappropriate rhythm in order to meet metabolic demand by enforcing aminimum heart rate. Implantable devices may also be used to treatcardiac rhythms that are too fast, with either anti-tachycardia pacingor the delivery of electrical shocks to terminate atrial or ventricularfibrillation.

Implantable devices have also been developed that affect the manner anddegree to which the heart chambers contract during a cardiac cycle inorder to promote the efficient pumping of blood. The heart pumps moreeffectively when the chambers contract in a coordinated manner, a resultnormally provided by the specialized conduction pathways in both theatria and the ventricles that enable the rapid conduction of excitation(i.e., depolarization) throughout the myocardium. These pathways conductexcitatory impulses from the sino-atrial node to the atrial myocardium,to the atrio-ventricular node, and thence to the ventricular myocardiumto result in a coordinated contraction of both atria and bothventricles. This both synchronizes the contractions of the muscle fibersof each chamber and synchronizes the contraction of each atrium orventricle with the contralateral atrium or ventricle. Without thesynchronization afforded by the normally functioning specializedconduction pathways, the heart's pumping efficiency is greatlydiminished. Pathology of these conduction pathways and otherinter-ventricular or intra-ventricular conduction deficits can be acausative factor in heart failure, which refers to a clinical syndromein which an abnormality of cardiac function causes cardiac output tofall below a level adequate to meet the metabolic demand of peripheraltissues. In order to treat these problems, implantable cardiac deviceshave been developed that provide appropriately timed electricalstimulation to one or more heart chambers in an attempt to improve thecoordination of atrial and/or ventricular contractions, termed cardiacresynchronization therapy (CRT). Ventricular resynchronization is usefulin treating heart failure because, although not directly inotropic,resynchronization can result in a more coordinated contraction of theventricles with improved pumping efficiency and increased cardiacoutput. Currently, a common form of CRT applies stimulation pulses toboth ventricles, either simultaneously or separated by a specifiedbiventricular offset interval, and after a specified atrio-ventriculardelay interval with respect to the detection of an intrinsic atrialcontraction or delivery of an atrial pace.

It has also been found that CRT can be beneficial in reducing thedeleterious ventricular remodeling which can occur in post-MI and heartfailure patients. Presumably, this occurs as a result of changes in thedistribution of wall stress experienced by the ventricles during thecardiac pumping cycle when CRT is applied. The degree to which a heartmuscle fiber is stretched before it contracts is termed the preload, andthe maximum tension and velocity of shortening of a muscle fiberincreases with increasing preload. When a myocardial region contractslate relative to other regions, the contraction of those opposingregions stretches the later contracting region and increases thepreload. The degree of tension or stress on a heart muscle fiber as itcontracts is termed the afterload. Because pressure within theventricles rises rapidly from a diastolic to a systolic value as bloodis pumped out into the aorta and pulmonary arteries, the part of theventricle that first contracts due to an excitatory stimulation pulsedoes so against a lower afterload than does a part of the ventriclecontracting later. Thus a myocardial region which contracts later thanother regions is subjected to both an increased preload and afterload.This situation is created frequently by the ventricular conductiondelays associated with heart failure and ventricular dysfunction due toan MI. The increased wall stress to the late-activating myocardialregions is most probably the trigger for ventricular remodeling. Bypacing one or more sites in a ventricle in a manner which causes a morecoordinated contraction, CRT provides pre-excitation of myocardialregions which would otherwise be activated later during systole andexperience increased wall stress. The pre-excitation of the remodeledregion relative to other regions unloads the region from mechanicalstress and allows reversal or prevention of remodeling to occur.

Neural Stimulation Therapies

One neural stimulation therapy involves treating hypertension bystimulating the baroreflex for sustained periods of time sufficient toreduce hypertension. Another therapy involves preventing and/or treatingventricular remodeling. Activity of the autonomic nervous system is atleast partly responsible for the ventricular remodeling which occurs asa consequence of an MI or due to heart failure. It has been demonstratedthat remodeling can be affected by pharmacological intervention with theuse of, for example, ACE inhibitors and beta-blockers. Pharmacologicaltreatment carries with it the risk of side effects, however, and it isalso difficult to modulate the effects of drugs in a precise manner.Embodiments of the present subject matter employ electrostimulatorymeans to modulate autonomic activity, referred to as anti-remodelingtherapy or ART. When delivered in conjunction with ventricularresynchronization pacing, such modulation of autonomic activity actssynergistically to reverse or prevent cardiac remodeling.

Increased sympathetic nervous system activity following ischemia oftenresults in increased exposure of the myocardium to epinephrine andnorepinephrine. These catecholamines activate intracellular pathwayswithin the myocytes, which lead to myocardial death and fibrosis.Stimulation of the parasympathetic nerves (vagus) inhibits this effect.According to various embodiments, the present subject matter selectivelyactivates the vagal cardiac nerves in addition to CRT in heart failurepatients to protect the myocardium from further remodeling andarrhythmogenesis. Other potential benefits of stimulating vagal cardiacnerves in addition to CRT include reducing inflammatory responsefollowing myocardial infarction, and reducing the electrical stimulationthreshold for defibrillating. For example, when a ventriculartachycardia is sensed, vagal nerve stimulation is applied, and then adefibrillation shock is applied. The vagal nerve stimulation allows thedefibrillation shock to be applied at less energy.

FIG. 9A illustrates an implantable medical device (IMD) with leadsextending into a heart; and FIGS. 9B and 9C illustrate an implantablemedical device with endocardial and epicardial leads, respectively. FIG.9A illustrates the IMD 928, including a pulse generator 929 and a header930. Leads 931 are attached to the header and are appropriately guidedto place electrodes on the lead in position to provide the desiredstimulation response.

As illustrated in FIGS. 9B and 9C, the heart 932 includes a superiorvena cava 933, an aortic arch 934, and a pulmonary artery 935. CRM leads936 pass nerve sites that can be stimulated in accordance with thepresent subject matter. FIG. 9B illustrates transvascularly fed leads,and FIG. 9C illustrates epicardial leads. Examples of electrodepositions are provided in the drawings by the symbol “X”. For example,CRM leads are capable of being intravascularly inserted through aperipheral vein and into the coronary sinus, and are capable of beingintravascularly inserted through a peripheral vein and through thetricuspid valve into the right ventricle of the heart (not expresslyshown in the figure) similar to a cardiac pacemaker lead, and continuefrom the right ventricle through the pulmonary valve into the pulmonaryartery. The coronary sinus and pulmonary artery are provided as examplesof vasculature proximate to the heart in which a lead can beintravascularly inserted to stimulate nerves within or proximate to thevasculature. Thus, according to various aspects of the present subjectmatter, nerves are stimulated in or around vasculature located proximateto the heart by at least one electrode intravascularly inserted therein.

FIGS. 10A and 10B illustrate the right side and left side of the heart,respectively, and further illustrate cardiac fat pads which provideneural targets for some neural stimulation therapies. FIG. 10Aillustrates the right atrium 1037, right ventricle 1038, sinoatrial node1039, superior vena cava 1033, inferior vena cava 1040, aorta 1041,right pulmonary veins 1042, and right pulmonary artery 1043. FIG. 10Aalso illustrates a cardiac fat pad 1044 between the superior vena cavaand aorta. Neural targets in the cardiac fat pad 1044 are stimulated insome embodiments using an electrode screwed into or otherwise placed inthe fat pad, and are stimulated in some embodiments using anintravenously-fed lead proximately positioned to the fat pad in a vesselsuch as the right pulmonary artery or superior vena cava, for example.FIG. 10B illustrates the left atrium 1045, left ventricle 1046, rightatrium 1037, right ventricle 1038, superior vena cava 1033, inferiorvena cava 1040, aorta 1041, right pulmonary veins 1042, left pulmonaryvein 1047, right pulmonary artery 1043, and coronary sinus 1048. FIG.10B also illustrates a cardiac fat pad 1049 located proximate to theright cardiac veins and a cardiac fat pad 1050 located proximate to theinferior vena cava and left atrium. Neural targets in the fat pad 1049are stimulated in some embodiments using an electrode screwed into thefat pad 1049, and are stimulated in some embodiments using anintravenously-fed lead proximately positioned to the fat pad in a vesselsuch as the right pulmonary artery 1043 or right pulmonary vein 1042,for example. Neural targets in the fat pad 1050 are stimulated in someembodiments using an electrode screwed into the fat pad, and arestimulated in some embodiments using an intravenously-fed leadproximately positioned to the fat pad in a vessel such as the inferiorvena cava 1040 or coronary sinus or a lead in the left atrium 1045, forexample.

In various embodiments, a neural stimulation channel uses a lead adaptedto be intravascularly disposed to transvascularly stimulate anappropriate nerve, e.g., near a baroreceptor to provide a sympatheticinhibition or near a parasympathetic nerve to provide parasympatheticstimulation. Some CRT devices include an atrial lead to pace and/orsense the right atrium, a right ventricle lead to pace and/or sense theright ventricle, and a left ventricle lead fed through the coronarysinus to a position to pace and/or sense the left ventricle, such asillustrated in FIGS. 9B and 9C. A lead within the coronary sinus iscapable of being used to transvascularly stimulate targetparasympathetic nerves anatomically located on the extravascular surfaceof the coronary sinus at a strength sufficient to elicit depolarizationof adjacent nerves, and is also capable of being used to deliver cardiacresynchronization therapy with appropriately timed pacing pulses at asite proximate to the left ventricle, for example.

Various lead embodiments implement a number of designs, including anexpandable stent-like electrode with a mesh surface dimensioned to abuta wall of a predetermined blood vessel, a coiled electrode(s), a fixedscrew-type electrode(s), and the like. Various embodiments place theelectrode(s) inside the blood vessel, into the wall of the blood vessel,or a combination of at least one electrode inside the blood vessel andat least one electrode into the wall of the blood vessel. The neuralstimulation electrode(s) can be integrated into the same lead used forCRT or in another lead in addition to CRT lead(s).

Intravascularly-fed leads adapted to transvascularly stimulate a targetoutside of the vessel, also referred to herein as transvascular leads,can be used to stimulate other nerve sites. For example, an embodimentfeeds a transvascular stimulation lead into the right azygos vein tostimulate the vagus nerve; and an embodiment feeds a transvascularstimulation lead into the internal jugular vein to stimulate the vagusnerve. Various embodiments use at least one lead intravascularly fedalong a lead path to transvascularly apply neural stimulation andelectrically stimulate a cardiac muscle, such as ventricular pacing, aspart of CRT.

Other transvascular locations have been mentioned with respect to FIGS.10A and 10B. Depending on the intravascular location of the neuralstimulation electrode(s), the right vagal branch, the left vagal branchor a combination of the right and left vagal branches are capable ofbeing stimulated. The left and right vagal branches innervate differentareas of the heart, and thus provide different results when stimulated.According to present knowledge, the right vagus nerve appears toinnervate the right side of the heart, including the right atrium andright ventricle, and the left vagus nerve appears to innervate the leftside of the heart, including the left atrium and left ventricle.Stimulation of the right vagus has more chronotropic effects because thesinus node is on the right side of the heart. Thus, various embodimentsselectively stimulate the right vagus nerve and/or the left vagus nerveto selectively control contractility, excitability, and inflammatoryresponse on the right and/or left side of the heart. Since the venoussystem is for the most part symmetrical, leads can be fed into anappropriate vessel to transvascularly stimulate the right or left vagusnerve. For example, a lead in the right internal jugular vein can beused to stimulate the right vagus nerve and a lead in the left internaljugular vein can be used to stimulate the left vagus nerve.

The stimulation electrode(s) are not in direct neural contact with thenerve when the transvascular approach to peripheral nerve stimulation isused. Thus, problems associated with neural inflammation and injurycommonly associated with direct contact electrodes are reduced.

In an embodiment of the invention, an implantable device for deliveringcardiac therapy to post-MI patients includes one or more pacing channelsfor delivering pacing pulses to one or more ventricular sites and aneural stimulation channel for stimulating nerves. The controller isprogrammed to deliver remodeling control therapy (RCT) by deliveringventricular pacing in a cardiac resynchronization mode which pre-excitesa region of the ventricular myocardium so as to mechanically unload thatregion during systole. The cardiac resynchronization therapy may bedelivered as biventricular pacing where one of the ventricles ispre-excited relative to the other as determined by a programmedbiventricular offset interval. In an embodiment in which patients sufferfrom delayed activation of the left ventricle, a left ventricle-onlyresynchronization pacing mode is employed. In another embodiment, thepacing therapy may be delivered as multi-site ventricular pacing whereat least one of the ventricles is paced at a plurality of sites so as topre-excite one or more of the sites relative to the other sites. In anycase, the ventricular pacing may be delivered in a non-atrial trackingmode where a ventricular escape interval is defined between ventricularpaces, or in an atrial tracking mode where the ventricular paces aredelivered after a defined atrio-ventricular escape interval following anatrial sense. In a patient who is chronotropically incompetent, anatrial pacing channel may also be provided for pacing the atria, withthe ventricular pace(s) delivered upon expiration of theatrio-ventricular escape interval following the atrial pace.

The controller is further programmed to deliver anti-remodeling therapy(ART) in conjunction with the RCT using a lead incorporating anelectrode adapted for disposition near an arterial baroreceptor orafferent nerve of a baroreflex arc. Stimulation of the baroreflex arcresults in inhibition of sympathetic activity. The electrode may beintravascularly positioned in a blood vessel or elsewhere proximate to abaroreceptor or afferent nerve such as in a pulmonary artery or acardiac fat pad. In another embodiment, the device delivers theanti-remodeling therapy by stimulating parasympathetic nerve activity.The electrode may be a nerve cuff electrode adapted for dispositionaround a parasympathetic nerve or an intravascular electrode fortransvascularly stimulating a parasympathetic nerve adjacent to a bloodvessel.

The device may be programmed to deliver RCT and ART in open-loop fashionwhere the RCT and ART are delivered simultaneously or separately atprogrammed intervals. In another embodiment, the device is programmed todeliver RCT and ART in closed-loop fashion, where the intensities of RCTand ART are modulated in accordance with an assessment of cardiacfunction performed by the controller.

The device may also separately modulate the intensities ofparasympathetic stimulation and sympathetic inhibition which aredelivered as part of the ART in accordance with the assessment ofcardiac function. Cardiac function may be assessed by the device usingseveral different modalities, either alone or in combination. In oneembodiment, the device incorporates a sensor for measuring cardiacoutput, and the controller is programmed to modulate the delivery of RCTand ART in accordance with the measured cardiac output. As describedabove, such a cardiac output sensor may be a trans-throracic impedancemeasuring circuit. A means for assessing cardiac function is an arterialblood pressure sensor, where the controller is programmed to modulatethe delivery of RCT and ART in accordance with the measured bloodpressure. The blood pressure sensor may take the form of a pressuretransducer and lead adapted for disposition within an artery. A measureof the patient's respiratory activity taken by a minute ventilationsensor may be used as a surrogate for blood pressure. Cardiac functionmay also be assessed by measuring the patient's exertion level (e.g.,using either a minute ventilation sensor or an accelerometer) togetherwith a measure of cardiac output and/or blood pressure, where thecontroller is then programmed to modulate the delivery of RCT and ART inaccordance with the combined measurements.

In an embodiment, the cardiac function assessment includes an assessmentof the patient's autonomic balance. Autonomic balance may be assesseddirectly with a sensing channel for measuring electrical activity insympathetic and parasympathetic nerves with appropriately positionedsensing electrodes, or if the patient is chronotropically competent, bymeasuring the intrinsic heart rate. As described above, measuring heartrate variability provides one means for assessing autonomic balance.Thus, the device may include circuitry for measuring and collecting timeintervals between successive intrinsic beats, referred to as a BBinterval, where the BB interval may be an interval between successiveatrial or ventricular senses. The device stores the collected intervalsas a discrete BB interval signal, filters the BB interval signal intodefined high and low frequency bands, and determines the signal power ofthe BB interval signal in each of the low and high frequency bands,referred to LF and HF, respectively. The device then computes an LF/HFratio and assesses autonomic balance by comparing the LF/HF ratio to aspecified threshold value.

Implantable Medical Device

Neural stimulation as described herein may be delivered by animplantable medical device configured to deliver only neural stimulationor to deliver other therapies such as bradycardia and/or cardiacresynchronization pacing, anti-tachyarrhythmia therapies such ascardioversion/defibrillation and/or anti-tachycardia pacing, and/orother therapies. An implantable device for delivering neural stimulationmay also incorporate one or more sensing channels for sensing cardiacelectrical activity and/or other physiological parameters. FIG. 11illustrates one embodiment of an implantable medical device 1128 fordelivering neural stimulation. The illustrated device includes a pulsegenerator 1129, and the pulse generator includes a controller 1151 tocommunicate with a memory 1152, a telemetry interface 1153 for use incommunicating with a programmer (not illustrated) of the implantablemedical device, and a stimulating/sensing hardware platform 1154. Theillustrated hardware platform includes a sense module 1155, a pacemodule 1156, and switches 1157 for use to operably connect the sensemodule and the pace module to the electrodes 1158A and 1158B. Theillustrated electrodes can be two electrodes on one lead, such as a tipand ring electrode or can be on separate leads. Additionally, one of theelectrodes can be a conductive portion, also referred to as a “can”, ofthe implantable medical device. The illustrated controller 1151 includesa pace/sense control module 1159 to control the switches and selectivelyenable the sense module to operably connect to the electrodes and sensea potential across the electrodes or the pace module to operably connectto the electrodes and apply a pacing signal to generate a pacingpotential between the electrodes to provide a desired electricalstimulus to a patient.

The illustrated controller 1151 includes a stimulation mode module 1160,and the illustrated pace module includes adjustable parameters 1161,such as, for example, amplitude, frequency, waveform, and pacing mode.The parameters of the pace module are able to be adjusted to selectivelyprovide a neural stimulation signal to the electrodes or a myocardialstimulation signal to the electrodes. In some embodiments, theparameters are able to be adjusted to selectively apply a neuralstimulation signal adapted to simultaneously provide myocardial andneural stimulation. According to various embodiments, the stimulationmode module is adapted to selectively apply CRM or myocardialstimulation using the electrodes, neural stimulation using theelectrodes, selectively alternate between myocardial and neuralstimulation using the electrodes according to a desired therapy, and/orsimultaneously apply both myocardial and neural stimulation using theelectrodes. The illustrated pace module includes adjustable parameters.

FIG. 12 is a simplified schematic illustration of a pace module 1256 forthe hardware platform illustrated in FIG. 11. The illustrated pacemodule includes a connection to a power supply 1261 (e.g. the battery ofthe implantable medical device), a pacing capacitor 1262, a chargeswitch 1263 and a discharge switch 1264. The charge switch is closed andthe discharge switch is opened when a charge is being stored from thepower supply onto the pacing capacitor, and the charge switch is openedand the discharge switch is closed to discharge the pacing capacitor asa pacing signal across the electrodes 1258A and 1258B. Some embodimentsinclude a discharge capacitor 1265 in series with the discharge circuitto attenuate the polarization voltages or after potentials which followthe application of a stimulation pulse to allow the sensing module tosense an intrinsic potential between the electrodes. Additionalcircuitry can be added to control and selectively adjust the potentialacross a charged capacitor, to adjust the duration and attenuation of adischarge signal, to adjust the waveform or morphology of the dischargesignal, to adjust the frequency of the discharge signal, and to provideburst pacing, for example. Those of ordinary skill in the art, uponreading and comprehending this disclosure, would understand how todesign a pace module to provide these adjustable parameters andincorporate the pace modules in a design of an implantable medicaldevice to allow the controller to selectively apply a signal tostimulate heart muscle, a signal to stimulate a neural response, and insome embodiments, a stimulation signal to provide both myocardial andneural stimulation.

The device illustrated in FIG. 12 shows a simplified device with signalpaths 1266A and 1266B to two electrodes. Each signal path used to applya stimulation signal and used to sense a stimulation signal can bereferred to as a channel. The implantable medical device can be designedwith switches to selectively connect one or more electrodes to eachchannel, or the implantable the electrode(s) can be designed such thateach channel is connected to predetermined electrode(s). Each channel iscapable of being individually controlled to send a stimulation signal toa predetermined electrode(s).

FIG. 13 illustrates a multi-channel embodiment of an implantable medicaldevice. The illustrated device 1328 includes a pulse generator 1329, andthe pulse generator includes a controller 1351 to communicate with amemory 1352, a telemetry interface 1353 for use in communicating with aprogrammer of the implantable medical device, and a hardware platform1354. The illustrated hardware platform includes a sense module 1355, astimulation or pace module 1356, and switches 1357 for use to operablyconnect the sense module and the pace module to a header 1330. Theheader includes one or more ports 1367 to receive a lead 1368. Each leadcan include one or more electrodes. The switches selectively providedesired connections between the sense and pace modules and the ports inthe header to provide desired pace channels between the pace module anddesired electrode(s) on the lead(s), and to provide desired sensechannels between the sense module and desired electrode(s) on thelead(s). In various embodiments, the can of the implantable medicaldevice is used as an electrode. Some embodiments of the pace module 1356include circuitry to independently and simultaneously providestimulation signals on multiple channels.

The controller includes a pace/sense control module to control theswitches and selectively enable the sense module to operably connect tothe electrodes and sense a potential across the electrodes or the pacemodule to operably connect to the electrodes and apply a pacing signalto generate a pacing potential between the electrodes to provide adesired electrical stimulus to a patient.

The illustrated controller includes a stimulation mode module 1360, andthe illustrated pace module 1356 includes adjustable stimulationparameters, including burst pacing parameters. The parameters of thepace module are able to be adjusted to selectively provide a neuralstimulation signal to selected electrodes or a myocardial stimulationsignal to selected electrodes. In some embodiments, the stimulationparameters of the pace module are able to be adjusted to selectivelyapply a neural stimulation signal adapted to simultaneously providemyocardial and neural stimulation. According to various embodiments, thestimulation mode module is adapted to selectively apply CRM ormyocardial stimulation using the electrodes, neural stimulation usingthe electrodes, selectively alternate between myocardial and neuralstimulation using the electrodes according to a desired therapy, and/orsimultaneously apply both myocardial and neural stimulation using theelectrodes.

The present subject matter is capable of providing neural and CRMstimulation therapies over one stimulation channel. Some embodimentsinvolve operating a CRM hardware platform, designed to capture heartmuscle, in a mode with stimulation parameters selected to depolarizenerves. For example, the CRM hardware platform may be operated in aburst pacing mode with a relatively low amplitude and a relatively highfrequency to provide neural stimulation.

Certain stimulation channels can be programmed to be dedicated to eitherCRM pacing or neural stimulation. In some embodiments, the stimulationchannels are able to intermittently and distinctly perform CRM pacingand neural stimulation. The different stimulation modes are performed atdifferent times, such as can be done with a time domain multiplexing ofthe stimulation channel. In some embodiments, the stimulation channelsare able to transmit a stimulation signal to simultaneously stimulatethe heart muscle and a desired neural response. For example, a higherfrequency neural stimulation signal can be modulated on a lowerfrequency CRM stimulation signal.

FIG. 15 illustrates a method to selectively provide myocardial and/orneural stimulation over a stimulation channel of the implantable medicaldevice. In the illustrated method, the desired stimulation is determinedat 1575. If CRM stimulation is desired, the process proceeds to 1576 andthe device enters a CRM stimulation mode. As represented at 1577, CRMstimulation parameters are used to apply CRM according to appropriateCRM algorithms using a pacing hardware platform. If, at 1575, it isdetermined that it is desired to provide neural stimulation therapy, theprocess proceeds to 1578 to enter a neural stimulation. As representedat 1579, neural stimulation parameters are used to apply neuralstimulation according to appropriate algorithms using the pacinghardware platform, which is the same platform used to provide CRMstimulation. According to some embodiments, if at 1575 it is desired tosimultaneously provide both CRM and neural stimulation, the processproceeds to 1580 where the devices enters a CRM and NS mode. Asrepresented at 1581, parameters are used to apply a stimulation signalto provide both CRM and NS pacing using the pacing platform of thedevice.

Lead Arrangements

The leads can be placed in a number of physiological locations. Someexamples have been provided above. An implantable device embodimentcontains one or more myocardial stimulation leads, as well as one ormore neural leads. Examples of neural stimulation leads include anexpandable stimulation lead, such as a stent-like lead, placed in thepulmonary artery in the proximity of a high concentration ofbaroreceptors; a transvascular lead placed proximal to one of thecardiac fat pads, or an epicardial lead placed in the cardiac fat pad;and a cuff electrode placed around a nerve trunk, such as the aortic,carotid or vagus nerve.

In an embodiment, myocardial stimulation and neural stimulation areprovided using the same lead(s) using different electrodes on thelead(s) or using the same electrodes on the lead(s). In someembodiments, the same lead can be used to simultaneously provide neuralstimulation and myocardial stimulation or to provide neural stimulationand to provide myocardial stimulation at different times than the neuralstimulation. In some embodiments, the leads are dedicated to eitherneural stimulation or stimulation of myocardial tissue. In embodimentsthat use dedicated leads, the controller of the implantable medicaldevice is able to select the stimulation mode for the pace channel tothe dedicated lead, and does not alternate between CRM and neuralstimulation modes.

Neural Stimulation Circuitry and Waveforms

The present subject matter provides a hardware platform that is capableof providing neural stimulation alone or in combination withCRM/myocardial stimulation. CRM therapy typically uses pacing signalswith a relatively larger amplitude and lower frequency than neuralstimulation signals, and the stimulation parameters can be appropriatelyadjusted for a desired stimulation mode. Some stimulation signals haveparameters sufficient for both CRM/myocardial stimulation and neuralstimulation. Thus, some embodiments of the present subject matterprovide a mode to provide simultaneous CRM and neural stimulation. Forexample, a CRM stimulation waveform can be designed to have harmonicfrequencies capable of stimulating nervous system.

FIGS. 14A, 14B and 14C illustrate examples of waveforms used to providemyocardial and neural stimulation. FIG. 14 A illustrates a stimulationwaveform applied between at least two electrodes that alternates betweena CRM stimulation pulse 1470 and a neural stimulation 1471, which isillustrated as a higher frequency signal. The CRM stimulation and neuralstimulation need not alternate, as some embodiments apply the CRM and/orneural stimulation only as a as-needed bases according to a closed-loopfeedback of sensed physiological parameter(s) (e.g. demand pacing forCRM stimulation, and sensed blood pressure for neural stimulation). Insuch embodiments, a time domain multiplexing scheme is used, where anyCRM stimulation to be applied is provided in one portion of a timingperiod and any neural stimulation to be applied is provided in anotherportion of the timing period.

FIG. 14B illustrates another stimulation waveform applied between atleast two electrodes. The illustrated waveform illustrates an example ofsimultaneous myocardial and neural stimulation. The waveform has asignal frequency sufficient to elicit depolarization of nerves. Theamplitude of the signal increases to a potential sufficient to captureheart muscle, such as illustrated at 1472.

FIG. 14C illustrates another waveform applied between at least twoelectrodes. The illustrated waveform provides CRM stimulation pulseswith an amplitude sufficient to capture heart muscle. The CRMstimulation signal attenuates after the heart muscle is captured at 1473to provide neural stimulation 1474 on the same electrodes.

In some embodiments, the stimulation channel is designated duringprogramming to either provide CRM or neural stimulation. In someembodiments, the stimulation channel is designated to either provide CRMor neural stimulation during the assembly of the implantable device viahardwiring, software, or logic circuits.

In one particular embodiment, the stimulation circuitry is configured todeliver a waveform for neural stimulation with the following approximateparameters:

frequency=20 Hz

pulse width=300 us

amplitude=1.5-2.0 mA

This waveform can be delivered as a pulse train applied eithercontinuously or intermittently (e.g., with a duty cycle=10 sec ON, 50sec OFF) in order to provide, for example, anti-remodeling therapy topost-MI or heart failure patients. Such stimulation may be appliedeither chronically or periodically in accordance with lapsed timeintervals or sensed physiological conditions. This waveform has beendemonstrated in pre-clinical studies to be a particularly effectiveanti-remodeling therapy when applied to the vagus nerve in the cervicalregion, where the stimulation may be applied through either a nerve cuffor a transvascular lead. The stimulating configuration for deliveringthe waveform may be any of the configurations described in this documentsuch as either a bipolar configuration or a unipolar configuration witha far-field subcutaneous return electrode. The stimulation circuitry maybe either dedicated to delivering neural stimulation or may beconfigured to also deliver waveforms suitable for CRM.

In another embodiment, a neural stimulation waveform such as describedin the preceding paragraph or elsewhere in this document may bedelivered with phases of alternating polarity, referred to herein asfirst and second phases. For example, the waveform may be delivered asmonophasic pulses with a bipolar stimulating configuration and with a“bipolar switch” so that the phase of the monophasic pulses isalternated in each consecutive pulse train. That is, a pulse train withmonophasic pulses having first phases of one polarity is then followedby a pulse train with monophasic pulses having second phases of theopposite polarity. FIGS. 16 and 17 show example waveforms as would beproduced by recording the potential between the stimulation electrodes.FIG. 16 shows an example of such a waveform in which a monophasic pulsetrain MPT1 having first phases FP1 of positive polarity is followed by amonophasic pulse train MPT2 having second phases SP1 of negativepolarity. In another embodiment, the stimulation circuitry may beconfigured to deliver a pulse train with biphasic pulses so that thefirst phase alternates with the second phase (i.e., each consecutivepulse in the train alternates in polarity). FIG. 17 shows an example ofa biphasic pulse train BPT1 having first phases FP2 and second phasesSP2 that alternate in polarity. Such biphasic pulse trains withalternating polarities or a series of monophasic pulses trains havingalternating polarities may be applied continuously or on a periodic orintermittent basis for a specified period of time.

FIGS. 20 and 21 illustrate different embodiments of circuitry fordelivering stimulation pulse trains as described above. In FIG. 20, acurrent source pulse output circuit 2003 outputs current pulses betweenstimulation electrodes 1258A and 1258B in accordance with command inputsfrom the controller 1351. The command inputs from the controller specifythe timing of the pulses, pulse widths, current amplitude, and polarity.FIG. 21 illustrates another embodiment in which a capacitive dischargepulse output circuit 2001 is used to output voltage pulses betweenstimulation electrodes 1258A and 1258B in accordance with command inputsfrom the controller 1351. In this embodiment, the command inputs fromthe controller specify the timing of the pulses, pulse widths, voltageamplitude, and pulse polarity. In order for the controller to specify avoltage amplitude that results in a desired current amplitude for thepulses, the lead impedance may be measured by lead impedance measurementcircuit 2002. The output capacitor of the pulse output circuit may thenbe charged to the appropriate voltage for each pulse. In order tomonitor the lead impedance, the controller is programmed toperiodically, or upon command from a user via telemetry, charge theoutput capacitor to a known voltage level, connect the output capacitorto the stimulation leads to deliver a stimulation pulse, and measure thetime it takes for the capacitor voltage to decay by a certain amount(e.g., to half of the initial value). In order to minimize patientdiscomfort, the lead impedance procedure should be performed using aslow a voltage as possible. In one embodiment, the controller isprogrammed to use a first voltage amplitude (e.g., 1 volt) and thencompare the measurement count (i.e., the capacitor decay time) to aspecified minimum value CntZMin. If the measurement count is belowCntZMin, the current delivered during the test is deemed too small forthe measurement to be accurate. A second measurement pulse is thendelivered at a higher second voltage (e.g., 2 volts). If that count isagain below CntZMin, a third measurement pulse is delivered at a stillhigher third voltage (e.g., 4 volts). With a typical stimulation lead,this procedure limits the measurement current to between roughly 1 mAand 0.6 mA.

FIGS. 18 and 19 show example waveforms as would be produced by thecapacitive discharge pulse output circuit, which correspond to thewaveforms of FIGS. 16 and 17, respectively. With a capacitive dischargepulse output circuit, the voltage amplitude of each pulse is notconstant as is the case with a current source pulse output circuit.FIGS. 18 and 19 thus show pulses in which the voltage rises to aninitial value and then decays as the output capacitor discharges. Also,the circuitry may incorporate a passive recharge between monophasicpulses in order to dissipate afterpotentials from the stimulationelectrodes. FIG. 18 shows such passive recharge cycles where the outputcircuitry is switched in a manner that causes the voltage between pulsesovershoots slightly in a direction opposite to the pulses and decays tozero as the afterpotentials between the stimulation electrodesdischarge. Passive recharge is not needed in the case of biphasic pulsesas each pulse discharges the afterpotential produced by the precedingpulse. FIG. 19 shows an interphase delay IPD between biphasic pulses. Incertain embodiments, it may be desirable to minimize or even eliminatethis delay.

In another embodiment, with either a biphasic pulse train or a series ofmonophasic pulse trains having alternating polarities, the stimulationparameters for the first and second phases may be adjusted separately.For example, the pulse widths and amplitudes for the first and secondphases of a biphasic pulse train may be selected to be the same ordifferent. In the case of a series of monophasic pulse trains havingalternating polarities, the pulse width, pulse amplitude, duty cycle,and frequency for each of the first and second phases may be selected tobe the same or different.

In another embodiment, advantage is taken of an empirical finding thatstimulation of the vagus nerve with pulses of different polarities canhave different effects. It has been found that vagal stimulation withalternating polarities, delivered as either a biphasic pulse train or bymonophasic pulse trains with alternating polarities, results not only inthe desired therapeutic effect for preventing or reversing cardiacremodeling as described above, but also with a reduction of undesiredside effects. Such side effects from vagal stimulation may include, forexample, hoarseness and coughing due to vagal innervation of the larynx.In order to achieve an optimum balance between therapeutic effects andundesired side effects, a neural stimulation waveform with alternatingpolarities may be applied over time while varying the pulse amplitudesand pulse widths for each polarity. As the pulse amplitudes and widthsare varied, a clinical determination may be made as to the therapeuticbenefit provided and the extent of any undesired side effects. Forexample, a biphasic pulse train or a series monophasic pulse trains withalternating polarities may be applied in which the pulse amplitude andpulse width for one polarity are titrated to a therapeutic dose. Thepulse amplitude and pulse width for the opposite polarity are thenadjusted to control the presence of side-effects. Which one of the twopolarities of the pulse train is responsible for producing therapeuticbenefits and which polarity is responsible for reducing side effects maybe determined empirically. Such a titration procedure may be performedby a clinician after implantation of the device, where the stimulationparameters such as pulse width and amplitude are adjusted via telemetry.The device could also be configured to automatically titrate thetherapeutic dose to a target amplitude within a specified period oftime. For example, such a titration could be performed rapidly duringthe first 1-2 weeks after an MI, which has been shown in pre-clinicalstudies to be the time where the greatest therapeutic benefit isachieved.

FIG. 22 is a system diagram of an exemplary neural stimulator. A battery220 provides power to the electronic circuit components of the device. Aprogrammable electronic controller 200 is interfaced to pulse generationcircuitry 205 and controls the output of neural stimulation pulses. Thecontroller may also be interfaced to sensing circuitry for sensingcardiac activity or other physiological variables. The controller 200may be made up of a microprocessor communicating with a memory, wherethe memory may comprise a ROM (read-only memory) for program storage anda RAM (random-access memory) for data storage. The controller could alsobe implemented by other types of logic circuitry (e.g., discretecomponents or programmable logic arrays) using a state machine type ofdesign. The controller includes circuitry for generating clock signalsused to keep track of lapsed time intervals and deliver neuralstimulation in accordance with a defined schedule. The pulse generationcircuitry 205 may be similar to that used in cardiac pacemakers or tothat described with reference to FIGS. 21 and 22. The pulse generationcircuitry delivers electrical stimulation pulses to a neural stimulationelectrode 215 (or electrodes in the case of a bipolar lead) via the lead210. The neural stimulation electrode may be, for example, a cuff ortransvascular electrode that may be disposed for stimulating the vagusnerve or a baroreceptor. A magnetically or tactilely actuated switch 240interfaced to the controller 200 allows the patient to initiate and/orstop the delivery of neural stimulation pulses. Once begun, the neuralstimulation pulses may continue to be delivered for a predeterminedlength of time or according to a predetermined schedule. The pulsefrequency, pulse width, pulse amplitude, pulse polarity, andbipolar/unipolar stimulation configuration in this embodiment areprogrammable parameters, the optimal settings of which depend upon thestimulation site and type of stimulation electrode. The device may alsobe equipped with different sensing modalities for sensing physiologicalvariables affected by neural stimulation. The device may then beprogrammed to use these variables in controlling the delivery of neuralstimulation. The device in FIG. 22 includes sensing circuitry 305connected to an electrode 315 (or electrodes in the case of a bipolarlead) via the lead 310 which may be intravenously disposed in the heartfor detecting cardiac electrical activity. The sensing circuitry 305allows the device to measure heart rate and to compute parametersderived therefrom such as heart rate variability or heart rateturbulence for use in controlling the delivery of neural stimulation.Separate sensing channels may be provided for detecting both atrial andventricular beats. For example, vagal stimulation slows the heart rate,and the device may be programmed to titrate the level of neuralstimulation delivered in response to a detected change in heart rate. Asneural stimulation may also affect respiratory rate, the device alsoincludes a minute ventilation sensor 250 and may be programmed tosimilarly titrate the level of neural stimulation delivered in responseto a detected change in respiratory rate. An accelerometer 260 is alsointerfaced to the controller which enables the device to detect heartsounds, the intensity of which may be reflective of myocardialcontractility. A pressure sensor could also be used for this purpose.The accelerometer 260 may also be used to detect coughing brought aboutby vagal stimulation. The device may then be programmed so that neuralstimulation is decreased or stopped if persistent coughing by thepatient is detected.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, and combinations of software and hardware. As such,the term module is intended to encompass software implementations,hardware implementations, and software and hardware implementations.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. For example,various embodiments combine two or more of the illustrated processes. Invarious embodiments, the methods provided above are implemented as acomputer data signal embodied in a carrier wave or propagated signal,that represents a sequence of instructions which, when executed by aprocessor cause the processor to perform the respective method. Invarious embodiments, methods provided above are implemented as a set ofinstructions contained on a computer-accessible medium capable ofdirecting a processor to perform the respective method. In variousembodiments, the medium is a magnetic medium, an electronic medium, oran optical medium.

Although specific embodiments have been illustrated and describedherein, it will be appreciated by those of ordinary skill in the artthat any arrangement which is calculated to achieve the same purpose maybe substituted for the specific embodiment shown. This application isintended to cover adaptations or variations of the present subjectmatter. It is to be understood that the above description is intended tobe illustrative, and not restrictive. Combinations of the aboveembodiments as well as combinations of portions of the above embodimentsin other embodiments will be apparent to those of skill in the art uponreviewing the above description. The scope of the present subject mattershould be determined with reference to the appended claims, along withthe full scope of equivalents to which such claims are entitled.

What is claimed is:
 1. An implantable device, comprising: stimulationcircuitry for delivering electrical stimulation to one or moreelectrodes adapted for disposition to stimulate the heart and vagusnerve; a controller connected to the stimulation circuitry forcontrolling the delivery of electrical stimulation by the stimulationcircuitry; an accelerometer interfaced to the controller: wherein thecontroller is configured to operate the stimulation circuitry so as todeliver both cardiac pacing pulses and neural stimulation pulses to theone or more electrodes; and, wherein the controller is configured todecrease or cease delivery of neural stimulation pulses if coughing isdetected from accelerometer signals.
 2. The device of claim 1 whereinthe controller is configured to deliver the neural stimulation pulsesand cardiac pacing pulses as a higher frequency neural stimulationsignal modulated on a lower frequency cardiac pacing signal.
 3. Thedevice of claim 1 wherein the controller is configured to delivercardiac pacing pulses alternated with neural stimulation pulses.
 4. Thedevice of claim 1 wherein the controller is configured so that thestimulation circuitry delivers neural stimulation pulses as a biphasicpulse train with alternating polarities.
 5. The device of claim 1wherein the controller is configured so that the stimulation circuitrydelivers neural stimulation pulses as a series of monophasic pulsetrains where the polarity of each consecutive pulse train alternates. 6.The device of claim 1 wherein the controller is configured to deliverneural stimulation pulses continuously.
 7. The device of claim 1 whereinthe controller is configured to deliver neural stimulation pulsesintermittently for specified periods of time.
 8. The device of claim 1wherein the controller is configured to deliver neural stimulationpulses intermittently with a duty cycle of 10 seconds ON and 50 secondsOFF.
 9. The device of claim 1 wherein the stimulation circuitry furthercomprises a current source pulse output circuit for outputting neuralstimulation pulses at a current amplitude specified by the controller.10. The device of claim 1 wherein the stimulation circuitry furthercomprises a capacitive discharge pulse output circuit and a leadimpedance measurement circuit for outputting pulses at a currentamplitude specified by the controller.
 11. The device of claim 1 whereinthe controller is configured so that the stimulation circuitry deliversneural stimulation pulses as a series of monophasic pulse trains wherethe polarity of each consecutive pulse train alternates with first andsecond phases and further wherein the pulse width, pulse amplitude, dutycycle, and frequency for each of the first and second phases areseparately adjustable.
 12. The device of claim 11 wherein the controlleris programmed such that the first phase is titrated to achieve a desiredtherapeutic benefit and the second phase is titrated to achieve adesired reduction in side effects.